Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

Direct-Acting Cholinergics

Pilocarpine is the most commonly prescribed miotic. It lowers IOP by directly stimulating the m3 muscarinic receptor of the ciliary muscle to increase aqueous outflow facility through a widened anterior chamber angle (176). Pilocarpine may also decrease aqueous humor production (177) and can decrease uveoscleral outflow (178), which may lead to a paradoxical rise in IOP when used in eyes with reduced trabecular outflow (179). It is available in concentrations ranging from 0.25 to 6% and is traditionally dosed four times a day, although twice-daily dosing may produce comparable IOP reduction if instillation is followed by nasolacrimal occlusion (180). Pilocarpine reduces IOP by 20 to 30% (181) and is additive to other IOP-lowering agents (98,182). It is also available in a high-viscosity acrylic vehicle or gel as a 4% concentration, which is typically used at bedtime. This formulation produces equivalent IOP reduction to pilocarpine drops taken four times daily with fewer side effects (183).

Ocular side effects are common with pilocarpine and are related to its effect on the ciliary and pupillary sphincter muscle. These include ciliary muscle spasm with resultant brow ache and induced myopia, especially in younger patients (184). Visual acuity and alterations in the visual field may result from pupillary miosis (185). Rarely, retinal detachment (186), vitreous hemorrhage (187), and macular hole formation (188) have been associated with pilocarpine use. Systemic side effects are uncommon with pilocarpine but can include diaphoresis, increased salivation, nausea, vomiting, and diarrhea.

Indirect-Acting Cholinergics

The indirect-acting cholinergics include echothiophate iodide and demecarium bromide, although only echothiophate iodide 0.125% is currently available in the USA.

This class of agents works by inhibiting cholinesterase in the eye (189). Reduction in IOP occurs through increased aqueous outflow facility in a mechanism similar to that described for pilocarpine. Studies have shown comparable IOP-lowering efficacy with pilocarpine (190). Longer duration of action (190) allows for twice-daily dosing for echothiophate. Although no longer commonly used in the USA, the indirect-acting agents are still a mainstay of therapy for the treatment of glaucoma in aphakia or pseudophakia across parts of Europe and Latin America.

A cataractogenic effect has been reported with long-term use of echothiophate (191). Other local side effects include development of iris cysts near the pupillary margin in children and the same parasympathomimetic effects, such as accommodative spasm and decreased vision from pupillary miosis, seen with pilocarpine. Systemic side effects are related to depletion of cholinesterase and pseudocholinesterase, which may begin within 2 weeks of initiation of therapy (192). Prolonged respiratory paralysis can occur in patients depleted of cholinesterase who undergo general anesthesia with succinylcholine as a muscle relaxant (192).

Dual-Mechanism Cholinergics

Carbachol produces direct muscarinic receptor stimulation within the eye along with inhibition of acetylchoinesterase. It is formulated in concentrations of 1.5 and

collagen and fibronectin making the ciliary muscle more permeable to aqueous humor (199). Relaxation of the ciliary muscle may also occur, further facilitating aqueous outflow and reduction of IOP (200).

The PGAs were first used for the treatment of glaucoma in the USA in 1996 with the introduction of latanoprost. Unoprostone (approved in 2000), bimatoprost (approved in 2001), and travoprost (approved in 2001) followed soon after. Since their introduction they have become a popular choice among clinicians for first-line therapy of glaucoma (22). The once-daily PGAs (latanoprost, bimatoprost, and travoprost) offer robust IOP reduction, excellent diurnal pressure control, and pose few, if any, systemic safety concerns. A recent prospective, multi-center trial involving over 400 patients with glaucoma or ocular hypertension has compared the safety and efficacy of the once-daily PGAs. After 3 months of therapy, statistically equivalent IOP reduction was found among the three agents with significantly more conjunctival hyperemia occurring in patients treated with bimatoprost compared with latanoprost (p = 0.001) (201).

Since its introduction into the US market in 1996, latanoprost has become the most widely prescribed drug for the treatment of glaucoma. Three large, multi-center trials involving 829 patients with glaucoma or ocular hypertension have compared oncedaily latanoprost 0.005% with twice-daily timolol 0.5% (202–204). After 6 months of treatment, IOP was significantly lower in those patients treated with latanoprost than timolol (6.7 ± 3.4 mmHg vs. 4.9 ± 2.9 mmHg, p = 0.001) (202). Analysis of phase III clinical trial data for latanoprost has shown a significantly higher percentage of nonresponders (IOP reduction less than 15% from baseline) among patients treated with timolol (31%) compared with latanoprost (20%) (205). Other studies have shown significantly greater IOP reduction for latanoprost when compared with dorzolamide (206) or brimonidine (207). Latanoprost has been shown to maintain its IOP-lowering efficacy after 2 years as monotherapy (208) and after 5 years as adjunctive therapy (209). Unlike timolol, it lowers IOP effectively at night as well as during daytime hours (92,210). It is also effective in juvenile-onset open-angle glaucoma (211), and in angle closure glaucoma when IOP remains elevated following peripheral iridectomy (212).

Latanoprost has been shown to be additive to timolol, with additional reductions in IOP ranging from 13 to 37% (213,214). Additivity to both oral (215) and topical (162) CAIs, and brimonidine (216) has been shown as well. Unoprostone does not appear to add additional IOP reduction when used adjunctively with latanoprost (217). Although animal studies have shown that miotic agents reduce PGF2 -induced hypotension (200), clinical trials have shown that pilocarpine does not impair the IOP-lowering capability of latanoprost (218). When added to pilocarpine-treated ocular hypertensive volunteers, latanoprost produced an additional reduction in IOP of 14.7% (219). There is evidence that patients who do not respond well to latanoprost (less than 10% IOP reduction after 6–8 weeks of therapy) may achieve better IOP control by switching to other once-daily PGAs (220).

Latanoprost is available as a 0.005% formulation and is dosed once-daily, usually in the evening. It has been approved for first-line usage by the Food and Drug Administration. Latanoprost is unstable when exposed to sunlight or high temperatures (221) and requires refrigeration for long-term (greater than 1 year) storage. Once opened by the patient, it can be stored at room temperature (up to 25ºC or 77ºF) for up to 6 weeks.

Bimatoprost was approved for use in the USA in 2001. It has been classified by some authors as a prostamide because of presence of an amide ethyl group, rather than an isopropyl ester, at the carboxy-terminal of the alpha carbon chain (see Fig. 1) (222). Bimatoprost is hydrolyzed to a lesser degree than the other PGAs into an active metabolite as it passes through the cornea (223). It is still not clear whether bimatoprost interacts as a free acid with the FP prostanoid receptor to lower IOP or works through another mechanism of action related to a different, as yet unidentified, receptor as an intact molecule (222,224). Bimatoprost lowers IOP primarily by increasing uveoscleral outflow, and to a lesser degree, trabecular outflow (196).

Studies have shown once-daily bimatoprost to be significantly more effective at lowering IOP than twice-daily timolol in patients with glaucoma or ocular hypertension (8.1 mmHg vs. 5.6 mmHg, p < 0.001) (225). Most comparison studies with latanoprost have shown comparable efficacy (201,226,227). A recent multicenter trial involving 269 patients with ocular hypertension or glaucoma has shown superiority of bimatoprost over latanoprost at all time points after 6 months of treatment (228). The mean IOPlowering effect of latanoprost in this study (24%) was significantly less than reported in earlier studies (30–35%) (201–204). In a 6-month comparison of bimatoprost and travoprost involving 157 patients with glaucoma or ocular hypertension, bimatoprost produced significantly greater IOP reduction at 9 a.m. (7.1 mmHg vs. 5.7 mmHg, p = 0.014). Reductions in IOP were clinically and statistically equivalent at 1 p.m. and 4 p.m. (229). Similar IOP-lowering efficacy between bimatoprost and dorzolamide 2%/timolol 0.5% fixed combination (Cosopt®) has been demonstrated in a prospective, multi-center, crossover comparison (230). Additivity to brimonidine (216), but not with pilocarpine, (231) has been shown with bimatoprost. It does not require refrigeration or protection from sunlight to maintain its potency (232) and is formulated as a 0.03% solution which is dosed once daily.

Travoprost, a full agonist at the FP prostanoid receptor (233), was also introduced for use in the US market in 2001. Like the other PGAs, travoprost increases uveoscleral outflow following interaction with the FP receptor (233). Phase III trials have demonstrated significantly greater reduction in IOP in patients treated with travoprost compared with timolol at 6 (234) and 9 (235) months after initiation of therapy. In a large, multicenter, 1-year trial comparing travoprost, latanoprost, and timolol, travoprost was found to produce significantly greater IOP reduction than timolol and equal or superior IOP reduction than latanoprost using pooled data (236). Comparable efficacy was found between travoprost and latanoprost at most of the individual time points evaluated throughout this 12-month study. This study also showed significantly greater IOP reduction with travoprost in blacks compared with that in nonblacks (236).

Post-marketing studies have shown that travoprost offers excellent diurnal pressure control with significant IOP reduction remaining for up to 84 h after its final dose (237,238). Additivity to timolol (103), brimonidine (239), and brinzolamide (240) has been shown. Recently, a new formulation of travoprost preserved with an ionic buffer system (sofZia™) rather than benzalkonium chloride (BAK) has received approval for clinical use in the USA. BAK-free travoprost (Travatan® Z) has shown equal IOPlowering efficacy compared with the original formulation (241). Both in vitro (242) and in vivo (243) studies have revealed significantly less corneal epithelial toxicity with

Travatan® Z when compared with other PGAs preserved with BAK. Like bimatoprost, travoprost does not require protection from heat or sunlight (244). It is formulated as a 0.004% solution and is dosed once daily.

Isopropyl unoprostone was introduced as a 0.12% solution in Japan in 1994 and became available in the USA as a 0.15% solution in 2000. Unlike the other PGAs, unoprostone is dosed twice daily. It also differs structurally from the other agents as a 22-carbon molecule (see Fig. 1). Comparison studies have revealed that unoprostone is less effective than timolol (245) and latanoprost (246). When used adjunctively with timolol, it shows similar efficacy to brimonidine or dorzolamide (247). Because of its more frequent dosing requirements and less potent efficacy, unoprostone has not enjoyed the same popularity as the other PGAs for the treatment of glaucoma. It is no longer available in the USA for clinical use.

Local, cosmetic side effects are common with all the PGAs. Reported rates of conjunctival hyperemia range from 5 to 15% for latanoprost (202–204), 15–45% for bimatoprost (225–227), 35–50% for travoprost (234–236), and 10–25% for unoprostone (245,246). Although common, conjunctival hyperemia associated with PGA use is typically mild and accounts for less than 5% of patient dropouts in most clinical trials. Eyelash growth, through stimulation of the growth phase of the hair cycle in the dermal papilla (248), has been reported to occur in 26–57% of patients (225,236). Increased iris pigmentation, most commonly in mixed color (brown-green) irides (202) has been reported to occur in 1.1–23% of patients using the once-daily PGAs (203,225,236) and less commonly with unoprostone (249). This increase in iris pigmentation is due to up-regulation of tyrosinase activity in iris melanocytes and subsequent increased production of melanin (250). Increased pigmentation of the eyelid skin may also occur with use of these agents (251,252).

Reactivation of herpetic keratitis has been reported with use of latanoprost (253) and bimatoprost (254). Exacerbation of anterior uveitis has also been seen with latanoprost (255). Cystoid macular edema (CME) has been associated with use of each of the PGAs (256). This class of agents should probably be avoided in patients with a history of complicated cataract surgery or other risk factors for CME.

In general, the PGAs pose few, if any, systemic safety concerns. Reported systemic side effects have been limited to transient headache and nonspecific upper respiratory symptoms. The PGAs have little to no clinical effect on the respiratory and cardiovascular systems, even in patients with asthma or chronic obstructive pulmonary disease

(257,258).

FIXED COMBINATION AGENTS

Therapy for glaucoma typically begins with the selection of a single agent for the reduction of IOP. Since the introduction of the PGAs, monotherapy has become a viable option for many patients. Single agent therapy offers several advantages to the patient including reduced risk of adverse events, decreased exposure to preservatives, and a convenient, simple medical regimen. Not all patients, however, can be adequately controlled on a single drug. A recent study showed that after 1 year of therapy, up to 30% of patients treated with a PGA required an additional medication for IOP control (259). Each of the other classes of glaucoma medications, including the 2-agonists

(216), -blockers (213,214), cholinergics (219), and CAIs (162) have been shown to produce additional IOP reduction when used in combination with a PGA. Adjunctive therapy, though, has limitations as well. Neelakantan and coworkers (260) found that adding a third or fourth agent to an existing glaucoma regimen resulted in a greater than 20% additional drop in IOP from baseline at 1 year only about 14% of the time. Significant dilution or “washout” of the initial drug may occur when a second drop is instilled too quickly after the first medication (26). Finally, increasing the complexity of a drug regimen can decrease patient compliance (24).

Fixed combination agents address many of the challenges associated with monoand concomitant therapy (see Table 3). By combining two different classes of glaucoma medications in one bottle, compliance may be improved through a simplified regimen, less exposure to preservatives occurs, and the potential for “washout” effect is eliminated. A fixed combination of timolol 0.5% and dorzolamide 2.0% (Cosopt®) became available for clinical use in 1998 and is dosed twice daily. Cosopt® has been shown to reduce IOP by 27–33% from baseline and to provide greater IOP reduction than either timolol or dorzolamide taken separately (161). A comparison study has shown that twice-daily Cosopt® and once-daily latanoprost produce equivalent reductions in IOP throughout 24 h in patients with glaucoma or ocular hypertension (261). Although no longer commonly used, a fixed combination of epinephrine 1% and pilocarpine 1–6% (E-pilo®), approved for four times daily use, has been available since the 1960s (182). A combination of timolol 0.5% and pilocarpine 2 and 4% (Timpilo®) is available for clinical use outside of the USA. When used twice daily, Timpilo-2® reduces IOP by up to 26% from baseline in patients with glaucoma or ocular hypertension (262). Recently, a fixed combination of timolol 0.5% and brimonidine 2.0% (Combigan®) has been developed. Combigan® has been shown to produce reductions in IOP ranging from 4.4 to 7.6 mmHg following 1 year of therapy, significantly greater than its individual components taken separately (263). Combigan® is dosed twice daily and is now available for clinical use in the USA.

Each of the once-daily PGAs (bimatoprost, latanoprost, and travoprost) has been formulated as fixed combination products with timolol 0.5%. The fixed combination latanoprost 0.005%/timolol 0.5% (Xalacom®) has been shown to produce significantly (p < 0.001) lower IOP (19.9 ± 3.4 mmHg) than either latanoprost (20.8 ± 4.6 mmHg) or timolol (23.4 ± 5.4 mmHg) taken separately (102). The fixed combination

travoprost 0.004%/timolol 0.5% (DuoTrav®) has been compared with its individual components taken concomitantly in a large, randomized, multi-center trial (264). DuoTrav® produced mean reductions in IOP, which were comparable with concomitant therapy (7.4–9.4 mmHg vs. 8.4–9.4 mmHg) and was equally safe and well tolerated after 3 months of treatment (264). The fixed combination bimatoprost 0.03%/timolol 0.5% (Ganfort®) has also been shown to provide equivalent IOP-lowering efficacy to its individual components taken concomitantly in a recent trial involving 445 patients with glaucoma or ocular hypertension (265). Each of the PGA/timolol-fixed combination products are dosed once daily. None are currently approved for use in the USA but are available in other parts of the world.

HYPEROSMOTIC AGENTS

Hyperosmotic agents are administered systemically (orally or intravenously) for the rapid reduction of IOP, typically in emergency situations such as acute-angle closure glaucoma. They work by reducing vitreous volume through the creation of an osmotic gradient between the blood and the ocular tissues (266). Fluid is drawn from the eye into the bloodstream because of the relatively higher osmolality of the blood. Onset of action is typically quite fast (less than 1 h). Duration of action is limited by the capacity of the drug to enter the eye. Smaller molecules, such as urea, enter the eye more readily and have a shorter duration of action than larger molecules, such as mannitol or glycerol. With disruption of the blood–aqueous barrier, which can occur in an inflamed eye, these drugs may not be able to create a large osmotic gradient between the blood and the ocular tissues, and therefore may be less effective. Although these agents are very effective at the acute reduction of IOP, they play no role in the chronic management of glaucoma.

Glycerol (osmoglyn) is administered orally as a 50% solution in a dosage of 1.0–1.5 g/kg (267). It begins to lower IOP within 10 min of administration and its effect lasts for up to 5 h (267). It is the only hyperosmotic agent to be metabolized with a caloric content of 4.32 kcal/g (267). Repeated administration may result in dehydration and acute hyperglycemic complications in patients with diabetes (268). Glycerol is no longer manufactured commercially but can often be formulated for short-term use by a local pharmacy. Another oral hyperosmotic agent, isosorbide (ismotic), is also no longer commercially manufactured for clinical use.

Mannitol is administered intravenously as a 25% solution in a dosage of 0.5–2.0 g/kg of body weight. Its onset of action is typically within 1 h and its IOP-lowering effect can last for up to 6 h (269). Efficacy is reportedly greater than glycerol (270). Mannitol may precipitate as crystals within the vial, which can be dissolved by warming the solution. Like glycerol, mannitol is typically administered in emergency situations but may also be used preoperatively before intraocular surgery or when glycerol is not tolerated. Another intravenous hyperosmotic agent, urea, is no longer used clinically.

Side effects are commonly seen with the hyperosmotic agents and can potentially be serious or even fatal. The undesirably sweet taste of the oral agents can be partially masked by administering them over ice or with juice. Nausea and vomiting may still occur and lead to loss of the medication. Diarrhea, headache, and confusion have also been reported (271). Diuresis is common, especially with the intravenous agents, and

can potentially lead to dehydration, acidemia, and serum electrolyte imbalances (271). Cardiovascular overload, potentially resulting in development of pulmonary edema and intracranial hemorrhage, may occur through transient increase in blood volume, especially in those patients with compromised renal function (272).

FUTURE DIRECTIONS

Reducing IOP can effectively prevent or delay the development or progression of glaucoma in many patients (273–275). Some patients, however, will continue to experience progression of their disease despite the achievement of an appropriate target IOP. This has prompted investigators to search for novel compounds that can offer protection for a vulnerable optic nerve independent of the effects of IOP. One such agent currently under study is memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist. The NMDA receptor functions as an ion channel within the central nervous system and allows entry of extracellular calcium into the cell for normal physiologic processes when stimulated by glutamate (276). Excessive stimulation of the NMDA receptor can lead to an overload of intracellular calcium within the neuron and programmed cell death through apoptosis (277). Some authors have reported elevated glutamate levels in the vitreous of patients with glaucoma (278) and in animal models of glaucoma (279). Theoretically, memantine may block excessive glutamate stimulation of the NMDA receptor of the retinal ganglion cell and thus help protect it from calcium-mediated apoptosis (280). Memantine is used to treat central nervous system disorders such as Parkinson and Alzheimer’s disease and is currently being studied as a neuroprotective agent for the treatment of glaucoma (281).

Nitric oxide, a gaseous second messenger molecule, appears to play an important role in normal physiologic processes of the eye including aqueous humor dynamics (282), ocular blood flow (283), and optic nerve function (284). Excess nitric oxide, on the contrary, may contribute to disease states such as uveitis (285) and glaucoma (286). Aminoguanidine, a selective inhibitor of inducible nitric oxide synthase, the enzyme responsible for production of excess nitric oxide in the optic nerve during periods of physiologic stress, has been shown to prevent retinal ganglion cell loss in an animal model of glaucoma (287). Currently, selective inhibitors of inducible nitric oxide synthase are being studied for use as potential neuroprotective agents for the treatment of glaucoma (288).

In addition to their IOP-lowering properties (289), calcium channel blockers may help protect a vulnerable optic nerve by improving ocular blood flow through vasodilation of vascular smooth muscle cells. Several small studies have shown reversal or lack of progression of visual field defects in patients with normal-tension glaucoma following treatment with oral calcium channel blockers (290,291). Improvement in color vision and visual field indices has been reported in patients with normal-tension glaucoma following treatment with nimodipine (292). Although early studies with calcium channel blockers look promising, these agents are not currently used for the routine management of glaucoma.

When injected intracamerally, ethacrynic acid, a sulfhydryl-reactive diuretic, has been shown to lower IOP significantly in patients with advanced glaucoma (293). This agent is thought to increase aqueous humor outflow facility by altering the cytoskeleton

of trabecular meshwork cells (294). Unfortunately, poor corneal penetration (295), corneal toxicity (296), and trabecular meshwork toxicity (297) have thus far precluded its clinical use for the management of glaucoma. Recent animal studies have shown promising early results for the use of several biologically active peptides for the reduction of IOP, including vasoactive intestinal peptide (298), atrial natriuretic peptides (299), and endothelins (300). Other investigators are currently exploring the potential role of immunomodulation in the treatment of glaucoma (301).

CONCLUSION

Medical therapy for glaucoma has changed dramatically over the past few years. Traditional agents, such as the cholinergics, the epinephrine, and the oral CAIs have been for the most part replaced by newer, safer, more effective agents, such as the PGAs, the 2-agonists, and the topical CAIs. Once a mainstay of first-line therapy, the -blockers have in many cases been supplanted from that role by the PGAs. For those patients who do not achieve an appropriate target pressure with monotherapy, mounting evidence in the literature supports the use of adjunctive agents for safe and effective additional IOP reduction. Currently, over 56,000 potential combinations of glaucoma drugs exist in our armamentarium (302). Although this array of choices may seem overwhelming, one benefit of the development of many new glaucoma agents in recent years is our current ability to truly individualize care when selecting a medical regimen for patients with glaucoma. Although reduction in IOP remains paramount for the treatment of glaucoma, research is currently underway to explore alternative modalities of therapy. Neuroprotection, immunomodulation, and genetic therapy offer potentially exciting avenues for treatment of this disease in the years to come.

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